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Published: December 06, 2010

r 2010 American Chemical Society 2786 dx.doi.org/10.1021/jf102567z|J. Agric. Food Chem. 2011, 59, 27862791

ARTICLE

pubs.acs.org/JAFC

Pyrethroids: Mammalian Metabolism and Toxicity

Hideo Kaneko*

Environmental Health Science Laboratory, Sumitomo Chemical Company Ltd., 1-98-3 Kasugadenaka, Konohana-ku Osaka, Japan

ABSTRACT: Synthetic pyrethroids, a major insecticide group, are used worldwide to control agricultural and household pests.Mammalian metabolism of pyrethroids was substantially launched in the 1960s and 1970s by the research groups of ProfessorCasida and Sumitomo Chemical Co., which made great contributions to the elucidation of their metabolic fates. They showed thatester hydrolysis and oxidation play predominant roles in mammalian metabolism of pyrethroids and that rapid metabolism leads tolow mammalian toxicity. These metabolic reactions are mediated by carboxylesterases and CYP isoforms, the resultant metabolitesthen undergoing various conjugation reactions. In general, there are substantially neither significant species differences in metabolicreactions of pyrethoids nor metabolic differences among their chiral isomers except with fenvalerate, one isomer of which yields alipophilic conjugate causing toxicity.

KEYWORDS: pyrethroids, mammalian metabolism, toxicity, fenvalerate

INTRODUCTION

First, I would like tocordially express my respect to Professor J. E.Casida for great achievements in pyrethroid research. In addition, Ioffer my thanks to the organizers of this symposium for inviting me.It is a great honor to have an opportunity to make a presentationabout pyrethroid metabolism and toxicity on this occasion.

Natural pyrethrins have been used for the control of mosqui-toes since ancient times, and many synthetic pyrethroids havebeen developed by modification of their chemical structures forbetter biological performance and stability in the environment.1

The primary target site of toxic actions of pyrethroids inmammals is reported to be voltage-sensitive sodium channels.

In addition, voltage-gated calcium channels, voltage-gated chlor-ide channels, and GABAA receptors may contribute to theneurotoxic effects of at least some pyrethroids.2

Synthetic pyrethroids can be classified into two categories:first and second generation.1 The characteristic feature of thefirst-generation pyrethroids, which are esters of chrysanthemicacid derivatives and alcohols having a furan ring and terminalside-chain moieties, is sensitivity to light, air, and temperature.Therefore, these pyrethroids have been used mainly for thecontrol of indoor pests. On the other hand, the second-genera-tion pyrethroids, generally 3-phenoxybenzyl alcohol derivatives,have excellent insecticidal activity as well as sufficient stability inthe environment. Thus, second-generation pyrethroids havebeen used worldwide for the control of agricultural pests.1

Pyrethroidsconstituteone major insecticide group commercially,and a 2008 survey3 indicated that the global market value forinsecticides was about $11000 million, with pyrethroids accountingfor 18%, following neonicotinoides (21%) and organophosphates(20%) by narrow margins. More than 20 pyrethroids have beenmarketed for agricultural pest control, and the leading ones in 2008were -cyhalothrin, deltamethrin, cypermethrin, bifenthrin, andR-cypermethrin in terms of total sales.3

From the historical viewpoint, mammalian metabolism studiesof pyrethroids can be roughly divided into three periods (firstperiod, from the late 1960s to the mid-1970s; second period,from the mid-1970s to 2000; third period, 2000 to the present).During the first period, mammalian metabolism studies of thefirst-generation pyrethroids was substantially launched by theresearch groups of Professor Casida and Sumitomo ChemicalCo., and these groups showed their metabolic reactions andidentification of metabolites mainly in rodents. In 1973, the bookPYRETHRUM, The Natural Insecticide (Academic Press, NewYork and London) edited by Professor Casida was published,which is the first, to my knowledge, to deal with metabolism and

toxicology of pyrethroids.In thesecondperiod, many in vivo andin vitro metabolism studiesof the first- and second-generation pyrethroids were carried out, andmetabolic fates were extensively examined in several mammalianspecies including humans, mostly using radiolabeled preparations.Furthermore, geometrical and chiral isomers of pyrethroids were thefocus of attention for better understanding of metabolic pathways.Since 2000(third period),molecular biologyhasmade great progress,and accordingly genetically expressed CYP isoforms or carboxyles-terases of animals or humans have become available. Furthermore,human hepatic microsomes or frozen hepatic cells have been on themarket. Therefore, it has become possible to determine whichenzymes are responsible for metabolic reactions and to detect clearspecies differences between humans and laboratory animals.1

OVERVIEW OF MAMMALIAN METABOLISM

So far, metabolic studies of about 30 synthetic pyrethroids,including their chiral and geometrical isomers, have been carriedout in mammals and reviewed.1 However, detailed metabolismdata have not been necessarily published in scientific journals. In

Special Issue: Casida Symposium

Received: July 8, 2010Revised: October 22, 2010Accepted: October 25, 2010

Part of the Symposium on Pesticide Toxicology in Honor of Professor JohnCasida. The following researchers from Sumitomo Chemical Co., Japan,wereinvolvedin pyrethriodmetabolism studies as postdoctoral researchersinJ. E. Casidas laboratory: Dr. Y. Nishizawa (1960s) and Dr. K. Ueda (1970s).

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2787 dx.doi.org/10.1021/jf102567z |J. Agric. Food Chem. 2011, 59, 27862791

Journal of Agricultural and Food Chemistry ARTICLE

some cases, the reports of joint World Health Organization/Food andAgricultural Organization (WHO/FAO) expert meetingson pesticideresidues andtheInternational ProgrammeonChemicalSafety (IPCS), Environmental Health Criteria (WHO), werereferred to ref 1.

Absorption, Tissue Distribution, and Excretion. Withregard to absorption, in general, oral absorption rates are rather high

in rats andmice, anddermalpenetration rates arelow. However, oralabsorption rates depend on the vehicles used for dosing. Aftersystemic absorption, pyrethroids and their metabolites do not showaccumulation in any specific tissues or organs.1 The acid and alcoholmoieties of pyrethroids are rapidly and completely excreted intourine and feces within several days after oral administration.1

However, the carbon derived from the CN group of pyrethroids,which are R-cyano-3-phenoxybenzyl alcohol derivatives, shows in-complete excretion and longer bioretention in skin and stomach.4-8

This slow andincomplete excretionis likely duetodistributionto theextracellular fluid and partial binding with serum albumin, as is thecase with endogenous thiocyanate.4,5

Metabolic Pathways. A review of the metabolic pathways ofabout 30 pyrethroids revealed that themajor metabolic reactions are

commonly oxidation, ester hydrolysis, and conjugation in all cases.1These metabolic reactions proceed in animals in first and secondsteps. As a first step, so-called phase I reactions occur, which areoxidation and ester hydrolysis. The second-step conjugation is aphase II reaction to generate hydrophilic and lipophilic forms.Hydrophilic conjugates are often found as glucuronides, sulfates,or amino acid conjugates, and these are readily excreted into urinedue to high water solubility. In less frequent cases, lipophilicconjugates are found, these generally showing longer bioretentionthan their hydrophilic ones. Although data in the public domain arelimited, metabolites of pyrethroids normally show less acute oraltoxicity than parent compounds so that rapid metabolism leads tolow mammalian toxicity.9

Metabolic Reactions. Phase I Reactions. Ester hydrolysisoccurs to a larger extent with the trans and primary alcoholderivatives as compared with the corresponding cis and secondaryalcohol derivatives, respectively. The chirality (1S or 1R) at the acidmoiety of phenothrin,10 tetramethrin,11 and permethrin12 does notsignificantly affect ester hydrolysis (Figure 1). Oxidation reactionsoccur on several sites of the acid and alcohol moieties, depending

on the chemical structure. For example, the trans methyl of theisobutenyl group in chrysanthemates is preferentially oxidized overthecis methyl group, and the 40-positionof the phenoxy ring is oxidi-zedto a larger extentas compared with other positions (Figure 2).13

Phase 2 Reactions. Hydrophilic conjugates found in mam-malian metabolism of pyrethroids are glucuronides, sulfates, andamino acid conjugates (Figure 3).1 3-Phenoxybenzoic acid (3-PBacid), a common metabolite from pyrethroids having a 3-phe-noxybenzyl alcohol or R-cyano-3-phenoxybenzyl alcohol in thealcohol moiety, shows remarkably diversified amino acid con-jugates: a glycine conjugate is the major form in sheep, cats, andgerbils; a taurine conjugate is found in mice; and a glycylvalinedipeptide conjugate is found in the mallard duck.14 In addition,thiocyanate and sulfonic acid conjugates have been reported.

Thiocyanate is formed by conversion of the CN ion releasedfrom ester hydrolysis of pyrethroids with theR-cyano-3-phenox-ybenzyl alcohol derivative.4-8 Sulfonic acid conjugates have asulfonic acid group incorporated into the double bond of the3,4,5,6-tetrahydrophthalimide moiety of tetramethrin and arereported to be formed in the intestinal tract by nonenzymaticallydirect addition of sulfonic acid.15 A mercapturic acid conjugateis documented to be involved in the metabolism of prallethrin(Figure 3).16

In addition, three types of lipophilic conjugates have beenreported from pyrethroid metabolism studies. These are choles-terol ester (fenvalerate),17,18 glyceride (a metabolite: 3-PBacid),19

and bile acid conjugates (fluvalinate) (Figure 4).20

Figure 1. Metabolic reaction 1: ester hydrolysis.
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METABOLIC DIFFERENCES AMONG OPTICALISOMERS OF PYRETHROIDS

In general, pyrethroids have chiral isomers due to the presenceof chiral centers. Whereas no substantial differences have been

described for absorption, excretion, or metabolic reactionsamong chiral isomers of phenothrin,10 tetramethrin,11 andpermethrin,12 fenvalerate shows a significant difference in for-mation of a lipophilic conjugate. It has four chiral isomers due tothe presence of two chiral carbons, and one of these, the BR (2R,RS)-isomer, yields a cholesterol ester conjugate from its acidmoiety (Figure 5).17 This conjugate is demonstrated to be acausative agent for granulomatous changes, which are observedin rats and mice when fenvalerate is dosed for a long time. 21 Inaddition, this chiral-specific formationof the cholesterol ester hasbeen demonstrated to be mediated by transesterification reac-tions of carboxylesterase(s) in microsomes, but not by any of thethree known biosynthetic pathways of endogenous cholesterol

esters (acyl-CoA:cholesterol O-acyltransferase (ACAT), lecithin:cholesterol O-acyltransferas (LCAT), or cholesterol esterase).22

This is the first example elucidated of a lipophilic conjugatecausing toxicity.2

METABOLISM IN HUMANS

In vitro comparative metabolism of14

C-trans-permethrin labeledin the alcohol moiety and 14C-trans-phenothrin labeled in the acidmoiety were carried out in human and rat hepatic microsomes andrevealed that both microsomes show similar HPLC radioautograms,indicating products derived from ester hydrolysis to be the majormetabolites.23Others fromoxidationreactions were relatively minor(Figure 6). Human and rat hepatic microsomes show comparableability to hydrolyze ester linkages and oxidize various sites ofpyrethroids, resulting in the formation of metabolites found inin vivo rat studies. Furthermore, we examined which CYP isoformsare responsible for the oxidation using 9 human and 14 rat CYPisoforms. It is shown that human CYP1A2, 2C19, 2C9, 2D6, 2E1,and 3A4 and rat CYP1A1, 2A1, 2C6, 2C11, 3A1, and 3A2 haverelatively high activity for trans-permethrin and that human

CYP2B6, 2C19, 2C9, and 2D6 and rat CYP1A1, 2C6, 2C11, and3A2 are more active for trans-phenothrin.23 These findings aregenerally similar to the results in other pyrethroids reportedpreviously.24,25 On the other hand, PBalc is more rapidly oxidizedat the 40-position of the ring by human CYP 2E1 than by human2C19 and 2D6 and by rat CYP 2E1 than by rat CYP1A1, 2C6,and 2C11.23 CYP2E1 is likely to play an important role in40-hydroxylation of the 3-phenoxybenzyl alcohol moiety.

SPECIES DIFFERENCES BETWEEN HUMANS ANDLABORATORY ANIMALS

Metabolism studies of pyrethroids in humans have been com-paratively limited, but the data obtained so far indicate that the

Figure 2. Metabolic reaction 2: oxidation.

Figure 3. Metabolic reaction 3: hydrophilic conjugates.
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reactions of pyrethroids are similar to those in rodents.26,27 That is,ester hydrolysis andoxidationare shared in common.However, it isreported that the absorption rate of pyrethroids through the skin isremarkably different between humans and rats and that humansshow much less skin penetration with cypermethrin, indicating thatrat models overestimate human skin penetration (i.e., penetrationrate (%) of dose: human in vivo, 1.2%, versus rat in vivo, 12%, for

24 h).28

This overestimation is similarly seen in dermal absorptionstudies of permethrin, bifenthrin, and deltamethrin.29,30 Withrespect to the enzymes involved in the metabolism of pyrethroids,CYP2C9 and 3A4in humans and 2C11 and 2C6 inrats seem toplaypredominant roles in oxidation reactions in terms of abundance andspecific activity.25 Major carboxylesterases for ester hydrolysis arehCE1 in humans and hydrolases A and B in rats, with a significantspecies difference found in serum esterase. Rat serum has highesterase activity for pyrethroids, whereashumans show substantiallyno activity.24,31What is important, however, is that it is likely thatthere are actually no poor metabolizers for pyrethroids in humans,because several CYP isoforms and carboxylesterase(s) are found tobe involved.

TOXICITY

Pyrethroids show moderate acute oral toxicity, and typicaltoxicological signs are tremors for type I (generally pyrethroidswithout the CN group in the alcohol moiety) and choreoathe-tosis with salivation (CS symptoms) for type II form (generallypyrethroids with the CN group in the alcohol moiety). Somepyrethroids are reported to show mixed clinical signs.2

Teratogenicity and genotoxicity results have generally beennegative;32 however, carcinogenicity studies have shown somepositive results. In some cases, the mode of action for carcino-genicity has been elucidated. As a typical example, metofluthrincan be illustrated.33 This pyrethroid causes hepatocellular tumorsin rats through nongenotoxic mechanisms involving CYP 2Binduction, demonstrated to be mediated by nuclear hormonereceptor CAR using RNAi technology. In addition, clusteringanalysis of transcriptomes shows similar results with both meto-fluthrin and phenobarbital. From the available results takentogether, metofluthrin induction of rat hepatic tumors does notappear to be relevant to the human case, as also shown withphenobarbital.33 Importantly, with regard to carcinogenicity, no

Figure 4. Metabolic reaction 4: lipophilic conjugates.

Figure 5. Metabolic differences among chiral isomers of fenvalerate-chiral specific formation of a cholesterol ester conjugate.
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reports have appeared regardingcancer in humans following oral,dermal, or inhalation exposure to pyrethroids.34 In addition, noreports were located regarding reproductive or developmentaleffects in humans following exposure to pyrethroids.34

CONCLUSIONS

Mammalian metabolism studies of many pyrethroid insecti-cides have been extensively carried out for more than 40 years;however, I think that there remain several important researchfields such as in vitro or in vivo comparative studies of pharma-cokinetics, age difference, metabolism in major tissues includingliver, kidney, and intestine, and metabolic enzymes and trans-porters involved in pyrethroid metabolism between humans androdents for better risk assessment and better extrapolation fromanimal data to human data. I believe that the above metabolismstudies will lead to further confirmation that pyrethroids are oneof the safest pesticide groups.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

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Figure 6. In vitro comparative metabolism in human and rat liver microsomes.
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